EP2192111A2 - Verfahren zur synthese substituierter tetracyclinverbindungen - Google Patents
Verfahren zur synthese substituierter tetracyclinverbindungen Download PDFInfo
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- EP2192111A2 EP2192111A2 EP10154210A EP10154210A EP2192111A2 EP 2192111 A2 EP2192111 A2 EP 2192111A2 EP 10154210 A EP10154210 A EP 10154210A EP 10154210 A EP10154210 A EP 10154210A EP 2192111 A2 EP2192111 A2 EP 2192111A2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/40—Ortho- or ortho- and peri-condensed systems containing four condensed rings
- C07C2603/42—Ortho- or ortho- and peri-condensed systems containing four condensed rings containing only six-membered rings
- C07C2603/44—Naphthacenes; Hydrogenated naphthacenes
Definitions
- New tetracycline analogues have also been investigated which may prove to be equal to or more effective than the originally introduced tetracycline compounds. Examples include U.S. Patent Nos. 2,980,584 ; 2,990,331 ; 3,062,717 ; 3,165,531 ; 3,454,697 ; 3,557,280 ; 3,674,859 ; 3,957,980 ; 4,018,889 ; 4,024,272 ; and 4,126,680 . These patents are representative of the range of pharmaceutically active tetracycline and tetracycline analogue compositions.
- tetracyclines were found to be highly effective pharmacologically against rickettsiae; a number of gram-positive and gram-negative bacteria; and the agents responsible for lymphogranuloma venereum, inclusion conjunctivitis, and psittacosis.
- tetracyclines became known as "broad spectrum" antibiotics.
- the tetracyclines as a class rapidly became widely used for therapeutic purposes.
- the invention generally pertains to methods for synthesizing substituted tetracycline compounds.
- the invention pertains, at least in part, to a method for synthesizing a carboxaldehyde substituted tetracycline compound by reacting a tetracycline reactive intermediate under appropriate conditions with carbon monoxide, a palladium catalyst, a phosphine ligand, a silane and a base, such that the carboxaldehyde substituted tetracycline compound is synthesized.
- the carboxaldehyde substituted tetracycline compound is a 7-, 9- and/or 10-carboxaldehyde substituted tetracycline compound.
- the tetracycline reactive intermediate is a halogenated tetracycline intermediate or a triflate substituted tetracycline intermediate.
- examples include an iodine substituted tetracycline intermediate, a chlorine substituted tetracycline intermediate, a bromine substituted tetracycline intermediate, an iodine and chlorine substituted tetracycline intermediate or a bromine and iodine substituted tetracycline intermediate.
- the compound is a 10-triflate substituted tetracycline intermediate.
- Other typical intermediates include 7-iodosancycline, 9-iododoxycycline, 7-chloro-9-iodosancycline or 7-bromo-9-iodosancycline.
- the method further comprises the step of precipitating the carboxaldehyde substituted tetracycline compound in a solvent, such as a non-polar solvent.
- a solvent such as a non-polar solvent.
- non-polar solvents include diethyl ether, MBTE, heptane and combinations thereof.
- the method also includes further reacting the carboxaldehyde substituted tetracycline compound under palladium catalyzed coupling conditions, hydrogenolysis conditions or reductive amination conditions.
- the invention pertains, at least in part, to a method for synthesizing a substituted tetracycline compound comprising reacting a reactive tetracycline intermediate with carbon monoxide, a palladium catalyst, a phosphine ligand, a silane and a base under appropriate conditions, wherein the reactive tetracycline intermediate is substituted at a first position with a first reactive moiety and substituted at a second position with a second reactive moiety, such that the first reactive moiety is replaced with a carboxaldehyde substituent and the second reactive moiety is unreacted.
- the first and second reactive moieties are selected from halogens and triflates.
- the first reactive moiety is iodine and the second reactive moiety is bromine.
- the reactive tetracycline intermediate is 7-bromo-9-iodosancycline.
- the method further comprises the step of precipitating the carboxaldehyde substituted tetracycline compound in a solvent, such as a non-polar solvent.
- a solvent such as a non-polar solvent.
- non-polar solvents include diethyl ether, MBTE, heptane and combinations thereof.
- the method further comprises the step of reacting the second reactive moiety under hydrogenolysis conditions or palladium catalyzed coupling conditions.
- the carboxaldehyde substituent is further reacted under reductive amination conditions to produce an aminomethyl substituted tetracycline compound; and the second reactive moiety is further reacted under palladium coupling conditions or under hydrogenolysis conditions.
- the aminomethyl substituted tetracycline compound is a 7- or 9-aminomethyl substituted tetracycline compound.
- the invention also relates to methods for synthesizing an aminomethyl substituted tetracycline compound comprising the steps of: a) reacting reactive tetracycline intermediate with carbon monoxide, a palladium catalyst, a phosphine ligand, a silane and a base under appropriate conditions, wherein the reactive tetracycline intermediate is substituted at a first position with a first reactive moiety and at a second position substituted with a second reactive moiety, wherein the first reactive moiety is replaced with a carboxaldehyde substituent; b) reacting the carboxaldehyde substituent under reductive amination conditions; and c) reacting the second reactive moiety under palladium coupling conditions or under hydrogenolysis conditions.
- the first reactive moiety is iodine and the second reactive moiety is bromine.
- the reactive tetracycline intermediate is 7-bromo-9-iodosancycline.
- the aminomethyl substituted tetracycline compound is a 7-or 9-aminomethyl substituted tetracycline compound.
- the method further comprises the step of precipitating the carboxaldehyde substituted tetracycline compound in a solvent, such as a non-polar solvent.
- a solvent such as a non-polar solvent.
- non-polar solvents include diethyl ether, MBTE, heptane and combinations thereof.
- the method of the invention further includes adding a Lewis acid with the carbon monoxide, the palladium catalyst, the phosphine ligand, the silane and the base.
- a Lewis acid is InCl 3 .
- a Lewis acid is used in the presence of a trialkylamine base.
- a palladium catalyst is Pd(OAc) 2 .
- a phosphine ligand is a xantphos ligand, such as xantphos.
- the silane include Ph 2 SiH 2 and Et 3 SiH.
- the base include carbonate bases and trialkylamine bases.
- the base can be sodium carbonate or diisopropylethylamine.
- the substituted tetracycline compound is synthesized in at least about 90% yield. In other examples, the substituted tetracycline compound is synthesized in about 91%, 92 %, 93%, 94%, 95%, 96%, 97%, 98%, or 99% yield.
- the invention generally pertains to methods for synthesizing substituted minocycline compounds.
- the invention pertains, at least in part, to a method for synthesizing a carboxaldehyde substituted minocycline compound by reacting a minocycline reactive intermediate under appropriate conditions with carbon monoxide, a palladium catalyst, a silane and a base, such that the carboxaldehyde substituted minocycline compound is synthesized.
- the palladium catalyst is PdCl 2 ( t Bu 2 PhP) 2 dichlorobis(di-tert-butylphenylphosphine palladium (II)] or PdCl 2 (DPEPhos) [bis(diphenylphosphinophenyl)ether palladium (II) chloride].
- the silane is Et 3 SiH.
- the base is a carbonate base, for example, sodium carbonate.
- the method further comprises the step of precipitating the carboxaldehyde substituted minocycline compound in a solvent, such as a non-polar solvent.
- a solvent such as a non-polar solvent.
- non-polar solvents include diethyl ether, MBTE, heptane and combinations thereof.
- the minocycline reactive intermediate is a halogenated minocycline intermediate, such as an iodine substituted minocycline intermediate, a chlorine substituted minocycline intermediate, or a bromine substituted minocycline intermediate.
- the compound is a 9-halogenated minocycline.
- 9-iodo minocycline is 9-iodo minocycline.
- the palladium catalyst is PdCl 2 ( t Bu 2 PhP) 2 dichlorobis(di-tert-butylphenylphosphine palladium (II)] or PdCl 2 (DPEPhos) [bis(diphenylphosphinophenyl)ether palladium (II) chloride].
- the silane is Et 3 SiH.
- the base is a carbonate base, for example, sodium carbonate.
- the invention pertains, at least in part, to a method for synthesizing a substituted minocycline compound by reacting a carboxaldehyde substituted minocycline compound under palladium catalyzed coupling conditions, hydrogenolysis conditions or reductive amination conditions.
- the invention also pertains, at least in part, to a method for synthesizing an aminomethyl substituted minocycline compound comprising the steps of: a) reacting a reactive minocycline intermediate with carbon monoxide, a palladium catalyst, a silane and a base under appropriate conditions, to form a carboxaldehyde substituted minocycline, and b) reacting the carboxaldehyde substituted minocycline under reductive amination conditions to form an aminomethyl substituted minocycline compound.
- the aminomethyl substituted minocycline compound is a 9-aminomethyl substituted minocycline compound.
- the palladium catalyst is PdCl 2 ( t Bu 2 PhP) 2 dichlorobis(di-tert-butylphenylphosphine palladium (II)] or PdCl 2 (DPEPhos) [bis(diphenylphosphinophenyl)ether palladium (II) chloride].
- the silane is Et 3 SiH.
- the base is a carbonate base, for example, sodium carbonate.
- the method further comprises the step of precipitating the carboxaldehyde substituted minocycline compound in a solvent, such as a non-polar solvent.
- a solvent such as a non-polar solvent.
- non-polar solvents include diethyl ether, MBTE, heptane and combinations thereof.
- the substituted minocycline compound is at least about 51 % pure.
- the substituted minocycline compound is about 55 %, 60 %, 65 %, 69 %, or 70% pure.
- This invention identifies an efficient route for the synthesis of 9-amino-methyl - substituted minocyclines, such as, for example, Compound 1:
- the regioselective functionalization of the D-ring site in the tetracycline class of therapeutic agents has been a significant hurdle to overcome in the development of practical synthetic methodology.
- the chemical diversity that can be achieved through selective functionalization can have a major impact in the discovery of novel compounds of pharmaceutical interest.
- Conventional techniques in the installment of regioselective chemical "handles" on positions C7 and C9 of the D-ring of tetracyclines typically entail the use of temporary blocking groups or other functionality (e.g., a NH 2 group), which can have major drawbacks in terms of regioselectivity, yield and practicality.
- the need for a methodology that can overcome these problems and complement well-established transformations would greatly benefit the development of new chemically diverse tetracycline compounds.
- silicon based reducing reagents in palladium catalyzed carbonylations is a viable alternative to organotin reducing agents.
- a silicon based reducing reagent is an attractive substitute for Bu 3 SnH and has proved to be satisfactory in carboxaldehyde formation with the tetracycline compounds.
- the desired carboxaldehyde tetracycline compounds may be obtained in high yields.
- the silicon based reducing agents display good qualities in comparison to Bu 3 SnH where the formation of the desired carboxaldehyde was highly favored over the premature reduced byproduct, which is observed to a significant extent in the Bu 3 SnH reaction.
- This new method for synthesizing substituted tetracyclines utilizes a less toxic reducing agent, as well as a low catalyst loading, and provides the product in desirable epimer purity and yield.
- the combination of improved yields, better toxicity profile and reduced labor costs should have a profound effect on the process scale synthesis of substituted tetracyclines.
- the catalyst derived from Pd(OAc 2 ) and the ligand xantphos are used in the formylation process with several common silanes.
- a variety of silicon reagents can be used under similar conditions as in the tin method, to produce the desired carboxaldehyde tetracycline in high yields with simple workup.
- the attribute of favored formation of the carboxaldehyde results in a significant improvement in the yield and the reaction times are shorter, which avoids epimerization of the desired product.
- the product can be easily isolated in acceptable purity by precipitating the product in a mixture MTBE and heptane.
- a palladium catalyzed carbonylation reaction was performed on 9-iodominocycline, which resulted in high yield with little if any epimerization.
- a multitude of other carboxaldehyde tetracyclines can also be produced from the following iodotetracyclines, which include 7-iodosacycline, 9-iododoxycycline, 7-chloro-9-iodosancycline, 7-bromo-9-iodosancycline and other C7 and or C9 combination tetracyclines.
- the C9 iodo group is regioselectively carbonylated where the C7 bromo group is unreactive under the indicated conditions.
- the reaction proceeds in excellent yield generating the 7-bromo-9-carboxaldehydesancycline compound, which is a useful intermediate in the preparation of a variety of novel compounds of pharmaceutical interest.
- the invention generally pertains to methods of synthesizing substituted tetracycline compounds. In one embodiment, the invention pertains, at least in part, to a method for synthesizing a carboxaldehyde substituted tetracycline compound.
- the invention generally pertains to methods of synthesizing substituted minocycline compounds.
- the invention pertains, at least in part, to a method for synthesizing a carboxaldehyde substituted minocycline compound.
- tetracycline compound includes substituted or unsubstituted tetracycline compounds or compounds with a similar ring structure to tetracycline.
- tetracycline compounds include: chlortetracycline, oxytetracycline, demeclocycline, methacycline, sancycline, chelocardin, rolitetracycline, lymecycline, apicycline; clomocycline, guamecycline, meglucycline, mepylcycline, minocycline, penimepicycline, pipacycline, etamocycline, penimocycline, etc.
- substituted tetracycline compound includes tetracycline compounds with one or more additional substituents, e . g ., at the 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 11a, 12, 12a or 13 position or at any other position which allows the substituted tetracycline, compound of the invention to perform its intended function.
- carboxaldehyde substituted tetracycline compound includes tetracycline compounds that are substituted with one or more aldehyde moieties ( e . g . -C(O)H) at the 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 11a, 12, 12a or 13 position or at any other position which allows the substituted tetracycline compound of the invention to perform its intended function.
- the carboxaldehyde substituted tetracycline compound is a 7-, 9- and/or 10-carboxaldehyde substituted tetracycline compound.
- the invention pertains to methods for synthesizing a carboxaldehyde substituted tetracycline by reacting a tetracycline reactive intermediate under appropriate conditions.
- appropriate conditions includes any conditions that are suitable for carrying out the reaction of converting the tetracycline reactive intermediate to the carboxaldehyde substituted tetracycline.
- Appropriate conditions include any suitable solvents, temperature, catalysts and reagents. A skilled artisan would readily be able to determine appropriate conditions for carrying out the methods of the invention.
- tetracycline reactive intermediate includes tetracycline compounds that are chemically reactive and undergo the desired reaction to form the substituted tetracycline compounds of the invention.
- the tetracycline reactive intermediate is a halogenated tetracycline intermediate, including an iodine substituted tetracycline intermediate ( e . g ., 7-iodosancycline, 9-iododoxycycline), a chlorine substituted tetracycline intermediate, a bromine substituted tetracycline intermediate, an iodine and chlorine substituted tetracycline intermediate ( e .
- the tetracycline reactive intermediate is a triflate substituted tetracycline intermediate ( e . g ., a 10-triflate substituted tetracycline intermediate).
- triflate includes the trifluoromethanesulfonate moiety and has the structure CF 3 SO 3 -.
- the tetracycline reactive intermediate is a halogenated minocycline intermediate, including an iodine, chlorine, or bromine substituted tetracycline intermediate ( e . g ., 9- iodominocycline).
- the invention pertains to methods for synthesizing a carboxaldehyde substituted tetracycline by reacting a tetracycline reactive intermediate under appropriate conditions with carbon monoxide, a palladium catalyst, a phosphine ligand, a silane and a base; such that the carboxaldehyde substituted tetracycline compound is synthesized.
- the invention pertains to methods for synthesizing a carboxaldehyde substituted tetracycline by reacting a tetracycline reactive intermediate under appropriate conditions with carbon monoxide, a palladium catalyst, a silane and a base; such that the carboxaldehyde substituted tetracycline compound is synthesized.
- palladium catalyst includes palladium (II) chloride (PdCl 2 ), bis(acetonitrile)dichloropalladium, palladium (II) acetate (Pd(OAc) 2 ), 2-(dicyclohexylphosphino)biphenyl, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex, bis(triphenylphosphine)palladium(II) dichloride, dichlorobis(tricyclohexylphosphine)palladium(II), bis(triphenylphosphine)palladium(II) diacetate, tris(dibenzylideneacetone)dipalladium(0), allylpalladium chloride dimer, tetrakis(triphenylphosphine)palladium(0), bis[tris(4-(heptadecafluoroocty
- palladium catalyst also includes any palladium catalyst that may be suitable for catalyzing the conversion of the tetracycline reactive intermediate to the carboxaldehyde substituted tetracycline compound.
- the palladium catalyst is palladium (II) acetate (Pd(OAc) 2 ).
- palladium catalyst also includes phosphine-containing palladium (II) catalysts such as PdCl 2 ( t Bu 2 PhP) 2 dichlorobis(di-tert-butylphenylphosphine palladium (II)] and PdCl 2 (DPEPhos) [bis(diphenylphosphinophenyl)ether palladium (II) chloride].
- phosphine-containing palladium (II) catalysts such as PdCl 2 ( t Bu 2 PhP) 2 dichlorobis(di-tert-butylphenylphosphine palladium (II)] and PdCl 2 (DPEPhos) [bis(diphenylphosphinophenyl)ether palladium (II) chloride].
- palladium catalyst also includes any palladium catalyst that may be suitable for catalyzing the conversion of the minocycline reactive intermediate to the carboxaldehyde substituted minocycline compound.
- phosphine ligand includes chelating non-chiral and chiral phosphine ligands that contain one or more phosphorus atoms trivalently bonded to an alkyl, alkenyl, alkynyl or aryl group.
- phosphine ligand also includes any phosphine ligand that may be suitable for use in the conversion of the tetracycline reactive intermediate to the carboxaldehyde substituted tetracycline compounds.
- the phosphine ligand is a xantphos ligand. Examples of xantphos ligands are shown in Table 2. In one particular embodiment, the xantphos ligand is xantphos.
- silane includes compounds with the chemical formula R 2 SiH 2 or R 3 SiH, in which each R is independently C 1 -C 10 branched or straight chain alkyl or C 5 -C 14 aryl.
- silanes include, for example, tripropylsilane (Pr 3 SiH), triisopropylsilane (iPr 1 SiH), benzyldimethylsilane, di- tert -butvlsilane (tBu 2 SiH 2 ), triethylsilane (Et 3 SiH), cyclohexyldimethylsilane, dimethylphenylsilane, diethylisopropylsilane, methylphenylsilane, dimethylisopropylsilane, diethylmethylsilane, dimethylethylsilane, diethylsilane (Et 2 SiH 2 ) , trioctylsilane, dimethyloctadec
- base includes chemical species that accept protons, such as carbonate bases and trialkylamines.
- carbonate bases include, for example, lithium carbonate, sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, strontium carbonate and lanthanum carbonate.
- the carbonate base is sodium carbonate.
- trialkylamines include, for example, trimethylamine, triethylamine, tributylamine, triisopropylamine, dimethylethylamine, diisopropylethylamine, diethylmethylamine, dimethylisopropylamine and dimethylbutylamine.
- the trialkylamine is diisopropylethylamine.
- the invention also pertains, at least in part, to methods for synthesizing a substituted tetracycline compound by reacting the carboxaldehyde substituted tetracycline compound under palladium catalyzed coupling conditions, hydrogenolysis conditions or reductive amination conditions.
- the C9 position of 7-bromo-9-iodosancycline can be selectively converted to a carboxaldehyde group selectively in a palladium catalyzed reductive carbonylation reaction.
- the reaction has excellent regioselectivity where the C9 iodo group reacts preferentially with Pd(PPh 3 ) 4 , Bu 3 SnH, and CO in NMP at 70 °C.
- the reaction proceeds in good yield generating the 7-bromo-9-carboxaldehydesancycline compound that is a useful intermediate in the preparation of a variety of novel compounds.
- the 7-bromo-9-carboxaldehydesancycline compound can participate in a reductive alkylation reaction to furnish C9 position aminomethyl derivatives.
- the C7 bromo group can then either be reduced under hydrogenolysis or the bromo group can participate in a variety of palladium catalyzed coupling processes to afford a multitude of C7 functionalized, C9 aminomethyl sancycline derivatives.
- the C9 position can be selectively coupled with an appropriate regioselective catalyst to furnish a 9 position alkyl, aryl, heterocycle, carbonyl or other type of functional groups.
- the C7 bromo group can either be reduced or coupled to generate a variety of C7 substituted sancycline derivatives.
- a variety of C7 and C9 position combination substituted compounds can be produced.
- the invention pertains a method for synthesizing a 9-substituted minocycline compound by reacting a reactive minocycline intermediate with carbon monoxide, a palladium catalyst, a silane and a base under appropriate conditions, wherein the reactive minocycline intermediate is substituted at the 9-position with a reactive moiety such that the reactive moiety is replaced with a carboxaldehyde substituent.
- palladium catalyzed coupling conditions refers to reaction conditions that include a palladium catalyst and converts a tetracycline compound of the invention to a substituted tetracycline compound by the formation of a carbon-carbon bond at the 7, 8, 9 and/or 10 position of the tetracycline compound or at any other position which allows the substituted tetracycline compound of the invention to perform its intended function.
- Examples of palladium catalyzed coupling conditions include reductive aminations, Stille reactions, Suzuki coupling reactions and Heck reactions.
- the palladium catalyzed coupling conditions includes an organotin compound ( e . g ., Bu 3 SnR', wherein R' is a C 1 -C 10 straight or branched chain alkyl, a C 2 -C 10 branched or straight chain alkenyl or alkynyl, or a C 5 -C 14 aryl group), a halogen or triflate substituted compound ( e .
- organotin compound e . g ., Bu 3 SnR', wherein R' is a C 1 -C 10 straight or branched chain alkyl, a C 2 -C 10 branched or straight chain alkenyl or alkynyl, or a C 5 -C 14 aryl group
- a halogen or triflate substituted compound e .
- the palladium catalyzed coupling conditions include an alkene ( e .
- R 1 C CR 2 , wherein R 1 and R 2 are each independently hydrogen, a C 1 -C 10 straight or branched chain alkyl, a C 2 -C 10 branched or straight chain alkenyl or alkynyl, or a C 5 -C 14 aryl group), a halogen or triflate substituted compound ( e . g ., aryl, benzyl, or vinyl halogen or triflate compound, such as, for example, a halogen substituted tetracycline compound or a triflate substituted tetracycline compound), a palladium catalyst ( e .
- the palladium catalyzed coupling reaction includes an aryl or vinyl boronic acid ( e .
- R 3 B(OH) 2 a compound of the formula R 3 B(OH) 2 in which R 3 may be, for example, a C 2 -C 10 branched or straight chain alkenyl or alkynyl, or a C 5 -C 14 aryl group), an aryl or vinyl halide or triflate ( e . g ., a halide or triflate substituted C 2 -C 10 branched or straight chain alkenyl, halide or triflate substituted C 5 -C 14 aryl group or a halogen substituted tetracycline compound or a triflate substituted tetracycline compound), a palladium catalyst ( e . g ., Pd(PPh 3 ) 4 ) and a solvent.
- R 3 may be, for example, a C 2 -C 10 branched or straight chain alkenyl or alkynyl, or a C 5 -C 14 aryl group
- R 3
- hydrogenolysis conditions refers to reaction conditions that convert a tetracycline compound of the invention to a substituted tetracycline compound by the addition of a molecule of hydrogen at the 7, 8, 9 and/or 10 position of the tetracycline compound or at any other position which allows the substituted tetracycline compound of the invention to perform its intended function.
- a skilled artisan would be able to readily determine other applicable hydrogenolysis conditions for the conversion of a tetracycline compound of the invention to a substituted tetracycline compound.
- hydrogenolysis conditions include a palladium catalyst ( e .
- reductive amination conditions refers to reaction conditions that involve the conversion of a carbonyl group (e . g ., a carboxaldehyde moiety) to an amine at the 7, 8, 9 and/or 10 position of the tetracycline compound or at any other position which allows the substituted tetracycline compound of the invention to perform its intended function.
- a skilled artisan would be able to readily determine other applicable reductive amination conditions for the conversion of a tetracycline compound of the invention to a substituted tetracycline compound.
- the reductive amination conditions include a reducing agent ( e .
- the reductive amination is performed in the presence of Pd/C. In some reactions, Pd/C is not included in the reductive amination reaction.
- the invention pertains a method for synthesizing a substituted tetracycline compound by reacting a reactive tetracycline intermediate with carbon monoxide, a palladium catalyst, a phosphine ligand, a silane and a base under appropriate conditions, wherein the reactive tetracycline intermediate is substituted at a first position with a first reactive moiety and substituted at a second position with a second reactive moiety, such that one of the first reactive moiety is replaced with a carboxaldehyde substituent and the second reactive moiety is unreacted.
- the invention pertains a method for synthesizing a 9-substituted minocycline compound by reacting a reactive minocycline intermediate with carbon monoxide, a palladium catalyst, a silane and a base under appropriate conditions, wherein the reactive minocycline intermediate is substituted at the 9-position with a reactive moiety such that the reactive moiety is replaced with a carboxaldehyde substituent.
- the method for synthesizing substituted tetracycline compounds provides the desired substituted tetracycline compounds in high yield.
- the yield is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%.
- the desired substituted tetracycline is synthesized in about quantitative yields.
- the method for synthesizing substituted minocycline compounds provides the desired substituted tetracycline compounds in high yield.
- the yield is at least about 90%, at least about 91 %, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%.
- the desired substituted tetracycline is synthesized in about quantitative yields.
- the invention pertains to a method for synthesizing an aminomethyl substituted tetracycline compound comprising the steps of: a) reacting a reactive tetracycline intermediate with carbon monoxide, a palladium catalyst, a silane and a base under appropriate conditions, wherein reactive tetracycline intermediate is substituted at the 9- position with a reactive moiety, wherein the reactive moiety is replaced with a carboxaldehyde substituent; b) reacting the carboxaldehyde substituent under reductive amination conditions.
- aminomethyl substituted tetracycline compound is a 9-aminomethyl substituted minocycline compound.
- the 9-aminomethyl minocycline compound synthesized by the method of the invention is substantially pure.
- the purity is greater than 50%, at least about 55%, at least about 60%, at least about 65%, at least about 69%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 99%.
- the method for synthesizing the tetracycline compounds of the invention further comprises the step of precipitating the substituted tetracycline compound in a solvent, such as, for example, a non-polar solvent.
- a solvent such as, for example, a non-polar solvent.
- non-polar solvent includes those solvents that have a dielectric constant of less than about 15. Examples of non-polar solvents include, for example, hexanes, heptane, benzene, toluene, diethyl ether (Et 2 O), chloroform, ethyl acetate, dichloromethane and methyl t-butyl ether (MBTE, or TMBE) or combinations thereof.
- the solvent is Et 2 O, MBTE, heptane or a combination thereof.
- This invention identifies an efficient route for the synthesis of 9-amino-methyl - substituted minocyclines, such as, for example, Compound 1:
- the method of the invention employs a selective palladium-phosphine catalyst, such as PdCl 2 (tBu 2 PhP) 2 or PdCl 2 (DPEPhos) for converting the 9-iodo compound to the 9-formyl compound.
- a selective palladium-phosphine catalyst such as PdCl 2 (tBu 2 PhP) 2 or PdCl 2 (DPEPhos) for converting the 9-iodo compound to the 9-formyl compound.
- PdCl 2 tBu 2 PhP
- DPEPhos PdCl 2
- the substituted tetracycline compound is of formula (I): wherein:
- the invention pertains to a method for synthesizing an aminomethyl substituted tetracycline compound comprising the steps of: a) reacting a reactive tetracycline intermediate with carbon monoxide, a palladium catalyst, a phosphine ligand, a silane and a base under appropriate conditions, wherein reactive tetracycline intermediate is substituted at a first position with a first reactive moiety and substituted at a second position with a second reactive moiety, wherein the first reactive moiety is replaced with a carboxaldehyde substituent; b) reacting the carboxaldehyde substituent under reductive amination conditions; and c) reacting the second reactive moiety under palladium coupling conditions or under hydrogenolysis conditions.
- the aminomethyl substituted tetracycline compound is a 9-aminomethyl substituted compound of formula (II): wherein:
- aminomethyl substituted tetracycline compound is a 7-aminomethyl substituted compound of formula (III): wherein:
- the method for synthesizing the tetracycline compounds of the invention further comprises adding a Lewis acid with the carbon monoxide, the palladium catalyst, the phosphine ligand, the silane and a base.
- the term "Lewis acid” includes aluminum (III) bromide (AlBr 3 ), aluminum (III) chloride (AlCl 3 ), boron (III) chloride (BCl 3 ), boron (III) fluoride (BF 3 ), iron (III) bromide, iron (III) chloride, tin (IV) chloride (SnCl 4 ), titanium (IV) chloride (TiCl 4 ) or indium (III) chloride (InCl 3 ).
- the Lewis acid is InCl 3 .
- the Lewis acid is used when the base is a trialkylamine ( e . g ., diisopropylethylamine).
- the method for synthesizing the tetracycline compounds of the invention further comprises the step of precipitating the substituted tetracycline compound in a solvent, such as, for example, a non-polar solvent.
- a solvent such as, for example, a non-polar solvent.
- non-polar solvent includes those solvents that have a dielectric constant of less than about 15. Examples of non-polar solvents include, for example, hexanes, heptane, benzene, toluene, diethyl ether (Et 2 O), chloroform, ethyl acetate, dichloromethane and methyl t-butyl ether (MBTE) or combinations thereof.
- the solvent is Et 2 O, MBTE, heptane or a combination thereof.
- alkyl includes saturated aliphatic groups, including straight-chain alkyl groups (e . g ., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.), branched-chain alkyl groups (isopropyl, tert-butyl, isobutyl, etc.), cycloalkyl (alicyclic) groups (cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
- straight-chain alkyl groups e . g ., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl
- alkyl further includes alkyl groups, which can further include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone.
- a straight chain or branched chain alkyl has 10 or fewer carbon atoms in its backbone ( e . g ., C 1 -C 10 for straight chain, C 3 -C 10 for branched chain).
- C 1 -C 10 includes alkyl groups containing 1 to 10 carbon atoms.
- substituted alkyl includes alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
- substituents can include, for example, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,
- Cycloalkyls can be further substituted, e . g ., with the substituents described above.
- An "alkylaryl” or an “arylalkyl” moiety is an alkyl substituted with an aryl ( e . g ., phenylmethyl (benzyl)).
- the term “alkyl” also includes the side chains of natural and unnatural amino acids.
- aryl includes groups, including 5- and 6-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, phenyl, pyrrole, furan, thiophene, thiazole, isothiaozole, imidazole, triazole, tetrazole, pyrazole, oxazole, isooxazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.
- aryl includes multicyclic aryl groups, e . g ., tricyclic, bicyclic, e .
- naphthalene benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, napthridine, indole, benzofuran, purine, benzofuran, deazapurine, or indolizine.
- aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles,” “heterocycles,” “heteroaryls” or “heteroaromatics.”
- the aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkyla
- alkenyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond.
- alkenyl includes straight-chain alkenyl groups (e. g., ethylenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc.), branched-chain alkenyl groups, cycloalkenyl (alicyclic) groups (cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), alkyl or alkenyl substituted cycloalkenyl groups, and cycloalkyl or cycloalkenyl substituted alkenyl groups.
- alkenyl includes straight-chain alkenyl groups (e. g., ethylenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl,
- alkenyl further includes alkenyl groups which include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone.
- a straight chain or branched chain alkenyl group has 10 or fewer carbon atoms in its backbone (e . g ., C 2 -C 10 or straight chain, C 3 -C 10 for branched chain).
- cycloalkenyl groups may have from 3-10 carbon atoms in their ring structure.
- C 2 -C 10 includes alkenyl groups containing 2 to 10 carbon atoms.
- substituted alkenyl includes alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
- substituents can include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),
- acyl includes compounds and moieties which contain the acyl radical (CH 3 CO-) or a carbonyl group. It includes substituted acyl moieties.
- substituted acyl includes acyl groups where one or more of the hydrogen atoms are replaced by for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including
- acylamino includes moieties wherein an acyl moiety is bonded to an amino group.
- the term includes alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups.
- aroyl includes compounds and moieties with an aryl or heteroaromatic moiety bound to a carbonyl group. Examples of aroyl groups include phenylcarboxy, naphthyl carboxy, etc.
- alkoxyalkyl includes alkyl groups, as described above, which further include oxygen, nitrogen or sulfur atoms replacing one or more carbons of the hydrocarbon backbone, e.g., oxygen, nitrogen or sulfur atoms.
- alkoxy includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom.
- alkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups.
- substituted alkoxy groups include halogenated alkoxy groups.
- the alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate
- amine or "amino” includes compounds where a nitrogen atom is covalently bonded to at least one carbon or heteroatom.
- alkyl amino includes groups and compounds wherein the nitrogen is bound to at least one additional alkyl group.
- dialkyl amino includes groups wherein the nitrogen atom is bound to at least two additional alkyl groups.
- arylamino and “diarylamino” include groups wherein the nitrogen is bound to at least one or two aryl groups, respectively.
- alkylarylamino alkylaminoaryl or “arylaminoalkyl” refers to an amino group which is bound to at least one alkyl group and at least one aryl group.
- alkaminoalkyl refers to an alkyl, alkenyl, or alkynyl group bound to a nitrogen atom which is also bound to an alkyl group.
- amide or "aminocarbonyl” includes compounds or moieties which contain a nitrogen atom which is bound to the carbon of a carbonyl or a thiocarbonyl group.
- the term includes "alkaminocarbonyl” or “alkylaminocarbonyl” groups which include alkyl, alkenyl, aryl or alkynyl groups bound to an amino group bound to a carbonyl group. It includes arylaminocarbonyl groups which include aryl or heteroaryl moieties bound to an amino group which is bound to the carbon of a carbonyl or thiocarbonyl group.
- alkylaminocarbonyl alkenylaminocarbonyl
- alkynylaminocarbonyl alkynylaminocarbonyl
- arylaminocarbonyl alkylcarbonylamino
- alkenylcarbonylamino alkynylcarbonylamino
- arylcarbonylamino alkylcarbonylamino
- alkenylcarbonylamino alkynylcarbonylamino
- arylcarbonylamino alkylcarbonylamino
- carbonyl or “carboxy” includes compounds and moieties which contain a carbon connected with a double bond to an oxygen atom.
- the carbonyl can be further substituted with any moiety which allows the compounds of the invention to perform its intended function.
- carbonyl moieties may be substituted with alkyls, alkenyls, alkynyls, aryls, alkoxy, aminos, etc.
- moieties which contain a carbonyl include aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, etc.
- formyl includes compounds with the formula -C(O)H.
- thiocarbonyl or "thiocarboxy” includes compounds and moieties which contain a carbon connected with a double bond to a sulfur atom.
- ether includes compounds or moieties which contain an oxygen bonded to two different carbon atoms or heteroatoms.
- alkoxyalkyl which refers to an alkyl, alkenyl, or alkynyl group covalently bonded to an oxygen atom which is covalently bonded to another alkyl group.
- esters includes compounds and moieties which contain a carbon or a heteroatom bound to an oxygen atom which is bonded to the carbon of a carbonyl group.
- ester includes alkoxycarboxy groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, etc.
- alkyl, alkenyl, or alkynyl groups are as defined above.
- thioether includes compounds and moieties which contain a sulfur atom bonded to two different carbon or hetero atoms.
- examples of thioethers include, but are not limited to alkthioalkyls, alkthioalkenyls, and alkthioalkynyls.
- alkthioalkyls include compounds with an alkyl, alkenyl, or alkynyl group bonded to a sulfur atom which is bonded to an alkyl group.
- alkthioalkenyls and alkthioalkynyls refer to compounds or moieties wherein an alkyl, alkenyl, or alkynyl group is bonded to a sulfur atom which is covalently bonded to an alkynyl group.
- hydroxy or "hydroxyl” includes groups with an -OH or -O - .
- halogen includes fluorine, bromine, chlorine, iodine, etc.
- perhalogenated generally refers to a moiety wherein all hydrogens are replaced by halogen atoms.
- polycyclyl or “polycyclic radical” refer to two or more cyclic rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings". Rings that are joined through non-adjacent atoms are termed "bridged" rings.
- Each of the rings of the polycycle can be substituted with such substituents as described above, as for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, alkylaminoacarbonyl, arylalkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, arylalkyl carbonyl, alkenylcarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and
- heteroatom includes atoms of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur and phosphorus.
- Method A A solution of anhydrous 9-iodominocycline freebase (14.6 g, 25.0 mmol), anhydrous InCl 3 (11.1 g, 50.0 mmol), anhydrous iPr 2 NEt (8.73 mL, 50.0 mmol), Pd(OAc) 2 (0.11 g, 0.50 mmol) and xantphos (0.29 g, 0.50 mmol) in anhydrous NMP (100 mL) in a dried 3-neck flask with internal thermometer was purged with CO to saturate the solution, then a large balloon of carbon monoxide was affixed to the top of the flask to maintain a positive pressure.
- Method B A solution of anhydrous 9-iodominocycline freebase (14.6 g, 25.0 mmol), anhydrous Na 2 CO 3 (10.6 g, 100.0 mmol), Pd(OAc) 2 (0.11 g, 0.50 mmol) and xantphos (0.29 g, 0.50 mmol) in anhydrous NMP (100 mL) in a dried 3-neck flask with internal thermometer was purged with CO to saturate the solution, then a large balloon of carbon monoxide was affixed to the top of the flask to maintain a positive pressure.
- NMP 100 mL
- reaction was cooled to ambient temperature and diluted with CH 3 CN (50 mL). The solution was transferred to another flask and while stirring vigorously Et 2 O (approx. 500 mL) was added slowly to precipitate the product. The resulting suspension was collected on a fine fritted funnel rinsing with Et 2 O. The product was further dried under high vacuum to afford 11.1 g in 99% yield.
- Method A A solution of anhydrous 7-bromo-9-iodosancycline freebase (15.5 g, 25.0 mmol), anhydrous InCl 3 (11.1 g, 50.0 mmol), anhydrous iPr 2 NEt (8.73 mL, 50.0 mmol), Pd(OAc) 2 (0.11 g, 0.50 mmol) and xantphos (0.58 g, 1.00 mmol) in anhydrous NMP (100 mL) in a dried 3-neck flask with internal thermometer was purged with CO to saturate the solution, then a large balloon of carbon monoxide was affixed to the top of the flask to maintain a positive pressure.
- 9-carboxaldehyde-7-bromo tetracycline (1) is reacted under reductive amination conditions (e . g ., a primary or secondary amine, DMF or 1,2-dichloroethane and NaCNBH 3 or Na(OAc) 2 ) to form a 9-aminomethyl-7-bromo tetracycline (2).
- reductive amination conditions e . g ., a primary or secondary amine, DMF or 1,2-dichloroethane and NaCNBH 3 or Na(OAc) 2
- the brominated intermediate is subjected to palladium catalyzed coupling conditions (an organotin reagent, a palladium catalyst and a solvent; an alkene, a palladium catalyst, a phosphine ligand and a base; or an aryl or vinyl boronic acid and a palladium catalyst) and a solvent to form 9-aminomethyl-7-substituted tetracycline compounds (3).
- the 9-aminomethyl-7-bromo tetracycline (2) can be subjected to hydrogenolysis conditions ( e . g ., a palladium catalyst, an ammonium formate and one or more solvents) to form 9-aminomethyl sancycline compounds.
- reaction was cooled to ambient temperature and diluted with CH 3 CN (50 mL). The solution was transferred to another flask and while stirring vigorously Et 2 O (approx. 500 mL) was added slowly to precipitate the product. The resulting suspension was collected on a fine fritted funnel rinsing with Et 2 O. The product was further dried under high vacuum to afford 11.1 g in 99% yield.
- a 2L pressure reactor equipped with heating mantle, mechanical stirring rod and stirrer bearing, temperature probe, addition funnel, condenser and gas manifold inlet valve was purged with CO (g).
- 625 mL 4/1 THF/DMF was charged to pressure reactor followed by 9-iodominocycline 70 g (120 mmol), Na 2 CO 3 24.18 g (228 mmol), and PdCl 2 [tBu 2 PhP] 2 0.76 g (1.2 mmol) and stirred with heavy agitation.
- reaction mixture was diluted with 10 % Na 2 SO 3 and filtered.
- the funnel was washed with MeOH and water giving totally 300 mL of filtrate.
- the assay of the crude Compound 1 produced by this invention was 69% compared to 50% from the hydroxymethylphthalamide process.
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- 2008-07-07 DK DK08826197.9T patent/DK2176216T3/da active
- 2008-07-07 CA CA2693376A patent/CA2693376A1/en not_active Abandoned
- 2008-07-07 WO PCT/US2008/008355 patent/WO2009009042A1/en active Application Filing
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Also Published As
Publication number | Publication date |
---|---|
HRP20120605T1 (hr) | 2012-09-30 |
KR20100042276A (ko) | 2010-04-23 |
ZA201000034B (en) | 2011-10-26 |
HK1139386A1 (en) | 2010-09-17 |
JP2011020996A (ja) | 2011-02-03 |
CN101811980A (zh) | 2010-08-25 |
JP2010532759A (ja) | 2010-10-14 |
EP2176216B1 (de) | 2012-04-25 |
ES2386926T3 (es) | 2012-09-06 |
BRPI0823405A2 (pt) | 2012-12-25 |
AU2008275701A1 (en) | 2009-01-15 |
WO2009009042A1 (en) | 2009-01-15 |
CA2693376A1 (en) | 2009-01-15 |
EA201070048A1 (ru) | 2010-10-29 |
BRPI0813990A2 (pt) | 2011-09-13 |
EP2192111A3 (de) | 2010-10-06 |
EP2176216A1 (de) | 2010-04-21 |
ZA201008646B (en) | 2012-02-29 |
US20090156842A1 (en) | 2009-06-18 |
ATE555079T1 (de) | 2012-05-15 |
DK2176216T3 (da) | 2012-07-30 |
PT2176216E (pt) | 2012-07-27 |
US20170283368A1 (en) | 2017-10-05 |
AU2010200845A1 (en) | 2010-04-01 |
US9522872B2 (en) | 2016-12-20 |
CN101784517A (zh) | 2010-07-21 |
AU2008275701B2 (en) | 2013-04-04 |
IL204133A0 (en) | 2011-07-31 |
AU2010200845B2 (en) | 2013-01-17 |
EA201070233A1 (ru) | 2010-08-30 |
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